Multiple sclerosis is a demyelinating disease affecting the central nervous system, primarily of young adults. It is a common disease which affects one in 2000 persons. Epidemiological studies have indicated that there is a higher risk of MS among family members of MS patients, but strict genetic inheritance has not been proven. Recent work has shown some correlation between susceptibility to MS and histocompatibility type. An experimental disease termed experimental allergic encephalomyelitis, EAE, has long been studied as a possible model for the human disease, MS. Using inbred populations of rats, we have recently shown that susceptibility to EAE depends in part on the presence of an autosomal dominant immune response gene, Ir-EAE, which is linked to the major histocompatibility locus of this species. When the genes of EAE susceptible and resistant rat strains are mixed by appropriate cross breeding, susceptibility to EAE still depends on the presence of the Ir-EAE gene. But now there are other factors which modify the disease process so that the symptoms may be very mild, or absent, even in a genetically susceptible individual. This sort of incomplete expression of a disease process which is controlled by a histocompatibility linked gene and modified by other genes, is exactly what would be predicted for human diseases which may be controlled by histocompatibility linked immune response genes. The purpose of this project is to determine the factors in the experimental disease which determine susceptibility and the severity of clinical course. Data obtained from these studies may lead to a rational form of immunotherapy for multiple sclerosis. BIBLIOGRAPHIC REFERENCES: Williams, R.M. and Moore, M.J.; Experimental allergic encephalomyelitis: diminished severity with the H-l allele of a non-susceptible strain; Federation Proceedings, FASEB 1975. Moore, M.J. and Williams, R.M.; Histocompatibility type and susceptibility to experimental allergic encephalomyelitis (EAE) in Lewis, BN, F1, F2, and reciprocal backcross rats; Neurology; April 1974.